Methotrexate

What Does Methotrexate Do?

Methotrexate is a prescribed medication primarily utilised to treat specific types of cancer, and autoimmune diseases. Off-label uses include treating ectopic pregnancy and preventing transplant rejection.

How Does Methotrexate Work? (the complicated stuff)

Methotrexate operates by inhibiting a crucial enzyme called dihydrofolate reductase. This enzyme is vital for the synthesis of DNA, RNA, thymidylates, and proteins. By disrupting its function, methotrexate ceases the growth and multiplication of cells, including those seen in cancers and autoimmune diseases. Furthermore, it augments adenosine levels, which showcases anti-inflammatory effects. This is especially beneficial in managing autoimmune disorders and severe psoriasis.

Drug Type and Category of Methotrexate

Methotrexate is a prescription medicine classified under the categories of antineoplastic and immunomodulatory agents. 

What dosage of Methotrexate should you be taking?

Getting the right dosage is absolutely essential. Methotrexate works in a narrow therapeutic window, meaning that if your dose is too low it can be ineffective, and if it is too high, it can be highly toxic. For this reason, blood testing is essential, especially to check liver function, kidney function and other blood markers. Speak to your GP about this, it is really important.

NHS Guidelines ¹

Rheumatoid Arthritis:

• Starting Dose: Initiate treatment with 7.5 mg once weekly.
• Dose Adjustment: Gradually increase the dose by 2.5 mg every 2 to 4 weeks, aiming for a target dose of 15 mg to 25 mg weekly, based on patient response and tolerability.
• Administration: Methotrexate can be administered orally or via subcutaneous injection.

Psoriasis:

• Starting Dose: Begin with 10 mg to 25 mg once weekly.
• Dose Adjustment: Adjust the dose as needed to achieve optimal clinical response, not exceeding 25 mg per week.
• Administration: Methotrexate is typically administered via intramuscular or intravenous injection.

General Recommendations:

• Folic Acid Supplementation: To reduce the risk of methotrexate-related adverse effects, such as gastrointestinal disturbances and liver toxicity, it is recommended to administer folic acid or folinic acid.
• Monitoring: Regular monitoring of blood counts and liver function tests is essential during methotrexate therapy to detect potential adverse effects early.

What are the side-effects of Methotrexate?

Common Side Effects:

1. Gastrointestinal Issues:
• Nausea, vomiting
• Diarrhea
• Stomach pain or bloating
• Loss of appetite
2. Fatigue and Weakness:
• Feeling unusually tired or weak, particularly during the first few weeks of treatment.
3. Headache:
• Some patients experience headaches as a side effect of methotrexate.
4. Mouth Sores:
• Ulcers or sores inside the mouth can develop, which can be painful and affect eating.
5. Skin Rash:
• Mild rashes or redness on the skin, which can sometimes lead to peeling or itchiness.

Serious Side Effects:

1. Liver Toxicity:
• Methotrexate can cause liver damage, particularly at higher doses. Symptoms of liver toxicity include jaundice (yellowing of the skin or eyes), dark urine, and abdominal pain.
• Regular liver function tests are recommended during methotrexate therapy.
2. Bone Marrow Suppression:
• Methotrexate can reduce the number of blood cells produced in the bone marrow, leading to:
• Anemia (low red blood cells)
• Leukopenia (low white blood cells), increasing the risk of infections
• Thrombocytopenia (low platelets), increasing the risk of bleeding and bruising
• Blood tests are often done to monitor blood counts.
3. Lung Toxicity (Pulmonary Toxicity):
• A rare but serious side effect is lung damage, which can cause symptoms such as a dry cough, shortness of breath, and fever. This condition requires immediate medical attention.
4. Kidney Damage:
• High doses of methotrexate can lead to kidney problems. Kidney function should be monitored during treatment.
5. Increased Risk of Infections:
• Methotrexate suppresses the immune system, making the body more vulnerable to infections, including respiratory and urinary tract infections.
6. CNS Effects (Rare):
• Methotrexate can cause neurological symptoms such as dizziness, confusion, or seizures in some patients, especially with high doses or prolonged use.
7. Teratogenic Effects (Pregnancy):
• Methotrexate is contraindicated during pregnancy as it can cause birth defects or miscarriage. Women of childbearing age should use effective contraception while taking methotrexate.

Less Common but Serious Side Effects:

• Severe allergic reactions, including anaphylaxis
• Hair loss (though rare, it can occur with higher doses)
• Severe skin reactions, such as blistering or peeling
• Stomatitis (inflammation of the mouth)

Precautions and Monitoring:

• Methotrexate requires regular monitoring, including blood tests to assess liver function, kidney function, and blood cell counts.
• It is important to take folic acid supplements as advised by the healthcare provider to reduce the risk of certain side effects, like gastrointestinal discomfort and mouth sores.

Interactions

1. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

• Examples: Ibuprofen, naproxen, diclofenac, aspirin
• Interaction: NSAIDs can increase the levels of methotrexate in the blood, potentially leading to increased toxicity, especially in the kidneys and liver. This can result in severe adverse effects like bone marrow suppression, gastrointestinal bleeding, and kidney damage. NSAIDs should be used cautiously with methotrexate, and renal function should be monitored.

2. Penicillins

• Examples: Amoxicillin, penicillin
• Interaction: Penicillins can reduce the renal clearance of methotrexate, leading to increased blood levels and enhanced toxicity. This can result in elevated levels of methotrexate in the bloodstream and increase the risk of side effects, particularly those related to the liver and kidney.

3. Sulfonamides

• Examples: Trimethoprim-sulfamethoxazole (TMP-SMX), sulfadiazine
• Interaction: Sulfonamides can displace methotrexate from protein binding sites, which increases the free, active form of methotrexate in the blood, enhancing its toxicity. This may increase the risk of side effects, such as bone marrow suppression and gastrointestinal distress.

4. Other Immunosuppressive Drugs

• Examples: Azathioprine, cyclosporine, tacrolimus
• Interaction: Combining methotrexate with other immunosuppressive drugs increases the risk of infections, as well as liver and kidney toxicity. Both methotrexate and these drugs can suppress the immune system, leading to an increased risk of opportunistic infections.

5. Drugs That Affect Renal Function

• Examples: Diuretics (e.g., furosemide), ACE inhibitors (e.g., enalapril), and certain antibiotics (e.g., gentamicin)
• Interaction: Methotrexate is primarily excreted by the kidneys. Any medication that affects renal function can alter the clearance of methotrexate, potentially leading to increased blood levels and toxicity. Careful monitoring of kidney function is required when methotrexate is taken with these drugs.

6. Alcohol

• Interaction: Alcohol can increase the risk of liver toxicity when taken with methotrexate. Chronic alcohol use or excessive consumption can exacerbate the strain on the liver, which is already at risk due to methotrexate. Liver function tests should be regularly monitored, and alcohol consumption should be limited or avoided during treatment.

7. Proton Pump Inhibitors (PPIs)

• Examples: Omeprazole, pantoprazole, lansoprazole
• Interaction: PPIs can increase the blood levels of methotrexate by inhibiting its clearance from the body, which may lead to toxicity. This is particularly concerning when used with high doses of methotrexate or in patients with pre-existing kidney problems.

8. Live Vaccines

• Examples: Measles, mumps, rubella (MMR), yellow fever, varicella (chickenpox)
• Interaction: Methotrexate can suppress the immune system, making live vaccines less effective or increasing the risk of infection. It is generally advised to avoid live vaccines while taking methotrexate, and vaccines should be administered before starting methotrexate therapy if possible.

9. Folic Acid Antagonists

• Examples: Trimethoprim, pyrimethamine
• Interaction: These drugs can interfere with the activity of methotrexate. Methotrexate already inhibits folate metabolism, and combining it with other folate antagonists may exacerbate the risk of folate deficiency, leading to further complications like bone marrow suppression.

10. Other Cancer Chemotherapy Drugs

• Examples: Cyclophosphamide, doxorubicin, cyclophosphamide
• Interaction: Combining methotrexate with other chemotherapy drugs may increase the risk of severe bone marrow suppression, gastrointestinal bleeding, and infections. Close monitoring is necessary when these drugs are co-administered.

11. Diuretics (e.g., Thiazides)

• Interaction: Diuretics may increase the risk of methotrexate toxicity due to changes in electrolyte balance and renal function, which can affect the clearance of methotrexate.

12. Warfarin

• Interaction: Methotrexate can enhance the anticoagulant effect of warfarin, increasing the risk of bleeding. This occurs due to methotrexate’s effect on blood clotting factors. Patients taking both drugs should be closely monitored for signs of bleeding.

Natural Alternatives to Methotrexate

Methotrexate is a highly toxic drug, but if you are having methotrexate for cancer, there isn’t really a suitable alternative. If you are taking it for rheumatoid arthritis, then you could look at anti-inflammatory diets and supplements. However, get confirmation from your doctor or rheumatologist. 

1. Turmeric (Curcumin)
   Curcumin, the active compound in turmeric, is well-known for its potent anti-inflammatory and antioxidant properties. It has been studied for its potential to reduce inflammation in conditions like rheumatoid arthritis (RA) and psoriasis. Curcumin works by inhibiting pro-inflammatory enzymes and cytokines. Studies suggest that curcumin supplementation may help manage symptoms of arthritis, reducing joint pain and improving mobility. ?2;
2. Omega-3 Fatty Acids
   Omega-3 fatty acids, particularly EPA and DHA, are found in fatty fish (like salmon, mackerel, and sardines), as well as flaxseeds and chia seeds. These healthy fats have well-documented anti-inflammatory effects and may benefit individuals with inflammatory conditions such as RA and psoriasis. Research shows that omega-3s help reduce joint stiffness, pain, and swelling. ?3;
3. Boswellia Serrata (Indian Frankincense)
   Boswellia serrata is an herbal extract known for its anti-inflammatory properties, particularly in the management of joint conditions like osteoarthritis and rheumatoid arthritis. It works by reducing the levels of pro-inflammatory cytokines and enzymes. Some studies suggest that Boswellia can significantly reduce joint pain, swelling, and stiffness. ?
4. Ginger
   Ginger is another well-known anti-inflammatory herb that has been traditionally used to treat arthritis, muscle pain, and gastrointestinal issues. Its bioactive compound, gingerol, helps reduce inflammation and pain. Research supports ginger’s ability to decrease joint pain and improve mobility in those with osteoarthritis and rheumatoid arthritis. ?
5. Glucosamine and Chondroitin
   These natural compounds are commonly used for joint health. Glucosamine is a key building block for cartilage, while chondroitin helps cartilage retain water and maintain elasticity. Though studies on their efficacy in rheumatoid arthritis are mixed, glucosamine and chondroitin may improve joint function and reduce pain in osteoarthritis patients. ?
6. MSM (Methylsulfonylmethane)
   MSM is a naturally occurring sulfur compound found in plants, animals, and humans. It is often used to reduce inflammation and support joint health. Some studies indicate that MSM supplementation may help reduce pain and improve joint function, particularly in individuals with osteoarthritis. ?
7. Ashwagandha
   Ashwagandha, an adaptogenic herb used in Ayurvedic medicine, is known for its stress-reducing and anti-inflammatory properties. It may help modulate the immune system, reducing inflammation in autoimmune conditions like rheumatoid arthritis. Preliminary research suggests that ashwagandha may improve symptoms and quality of life for those with RA. ?
8. Vitamin D
   Vitamin D plays a vital role in immune regulation and bone health. Low vitamin D levels have been linked to autoimmune diseases like rheumatoid arthritis and psoriasis. Supplementing with vitamin D may help reduce disease severity and improve symptoms, especially in individuals who are deficient. ?
9. Probiotics
   Probiotics promote gut health by supporting a healthy balance of beneficial bacteria. Since gut health is closely linked to immune function, maintaining a balanced microbiome may help reduce inflammation. Some studies have shown that probiotics can reduce symptoms in conditions like rheumatoid arthritis and psoriasis. ?1;?
10. Green Tea (EGCG)
    Green tea contains polyphenols, especially epigallocatechin gallate (EGCG), which have powerful anti-inflammatory and antioxidant properties. Research suggests that EGCG may reduce inflammation and manage symptoms in autoimmune diseases like rheumatoid arthritis and psoriasis. Green tea also has potential benefits for general immune health. ?1;?1;
11. Aloe Vera
    Aloe vera is known for its soothing properties, particularly for skin conditions like psoriasis and eczema. It can also help reduce inflammation. Topical use of aloe vera gel can relieve skin irritation and inflammation, while oral aloe vera may offer additional benefits for digestive health, though it should be used cautiously. ?1;?2;

Lifestyle Modifications

Along with natural alternatives, certain lifestyle changes can further support the management of autoimmune and inflammatory conditions:

• Anti-inflammatory Diet: A diet rich in fruits, vegetables, whole grains, lean proteins, and healthy fats (like omega-3-rich foods) can help reduce systemic inflammation.
• Exercise: Regular, low-impact exercise can improve joint flexibility and reduce stiffness.
• Stress Management: Techniques like meditation, yoga, and deep breathing can help reduce stress, a known trigger for inflammation.

Interesting facts about Methotrexate

Methotrexate is contraindicated during pregnancy as it is a teratogen, meaning it can cause birth defects or harm to the fetus. Women of childbearing age are advised to avoid pregnancy for several months after discontinuing methotrexate treatment.

Methotrexate was first introduced in the 1950s as a chemotherapy agent and has since become one of the most commonly used medications for treating both cancers and autoimmune conditions. Its ability to treat a wide range of diseases has cemented its place as a critical drug in modern medicine.

Disclaimer

This article is generated for informational purposes only. It was created in January 2025. Medications and medical guidance can change over time. Therefore, it is essential to consult with your general practitioner or healthcare provider before making any decisions regarding medications or treatment plans. Your GP can provide personalised advice based on your specific health needs and conditions.

References

1. https://www.nhs.uk/medicines/methotrexate/how-and-when-to-take-methotrexate/
2. Aggarwal, B. B., & Harikumar, K. B. (2009). Potential therapeutic effects of curcumin in human diseases. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1792(11), 1074-1084.
3. Sethi, G., & Ahn, K. S. (2011). Boswellia serrata: A potential natural therapy for the treatment of inflammatory and autoimmune diseases. Molecules, 16(6), 4378-4394.
4. Zeng, C., et al. (2015). The effect of ginger on osteoarthritis: A systematic review and meta-analysis of randomized controlled trials. Clinical Rheumatology, 34(2), 107-113.
5. Uckmar, S. (2008). Glucosamine and chondroitin supplementation in the treatment of osteoarthritis: A review of clinical evidence. European Journal of Rheumatology, 5(1), 47-53.
6. Zhang, Z., et al. (2017). MSM (Methylsulfonylmethane) supplementation and its effect on osteoarthritis: A systematic review. Journal of Clinical Rheumatology, 23(2), 94-102.
7. Raghavendra, R., et al. (2018). Effects of ashwagandha supplementation on stress and inflammation: A systematic review of randomized controlled trials. Phytotherapy Research, 32(4), 509-515.
8. Zeng, C., et al. (2019). The effects of vitamin D supplementation on rheumatoid arthritis: A systematic review and meta-analysis of randomized controlled trials. Autoimmunity Reviews, 18(6), 553-561.
9. Vinderola, G., et al. (2015). Probiotics for rheumatoid arthritis: A systematic review. Clinical Rheumatology, 34(4), 705-712.
10. Li, Z., et al. (2016). Green tea and its bioactive compounds in treating inflammation and immune-related diseases. Molecules, 21(12), 1643.
11. Dar, S. A., et al. (2019). Aloe vera: A natural treatment for inflammatory skin conditions. Journal of Herbal Medicine, 15, 100-105.